Paternal exposure to dioxins and offspring sex ratio distortion Project Summary/Abstract It is widely recognized that the rates of certain male reproductive disorders (such as impaired semen quality, testicular cancer, cryptorchidism, and hypospadias) are increasing and that these changes may be caused in large part by toxic substances in the environment. In this proposal, one of these specific effects, the complex biological mechanism of sex ratio distortion caused in the offspring of human and animal males exposed to 2,3,7,8-tetrachlorodibenzo-p-dioxin (TCDD or dioxin), will be elucidated. The broad, long-term goal is to define the mechanism that causes transmission distortion in the sex ratios of offspring sired by male mammals that have been exposed to compounds such as TCDD. The hypothesis to be tested is: Certain environmental toxicants decrease the relative effectiveness of Y sperm by altering the ability of conjoined, synchronously developing haploid spermatids to share RNA and/or proteins across intercellular bridges or by differentially impacting gene expression from the X chromosome- bearing spermatids (X spermatids) or Y chromosome-bearing spermatids (Y spermatids). Specific Aim 1 is to enhance the experimental conditions for the study of sex ratio transmission distortion resulting from paternal dioxin exposure. The hypothesis to be tested is: As a consequence of TCDD exposure, inbred strains of mice that express highly responsive AHRs will exhibit greater sex ratio distortion than strains that have AHRs that are less responsive to TCDD. We will optimize the conditions for observing the sex ratio distortion and expect to find that AHR is required for the TCDD-induced sex ratio distortion. Specific Aim 2 is to elucidate the differences in specific mRNA levels between X and Y spermatids that have or have not been exposed to TCDD. The hypothesis to be tested is: TCDD, acting through the AHR, alters mRNA levels of a gene or genes affecting the relative functionality the X and Y sperm. We anticipate that specific genes are differentially expressed that influence the ability of X or Y sperm to fertilize an egg. Producing the proper sex ratio in offspring is important to biomedicine (human health consequences), ecology (preservation of species), and, potentially, agriculture (as a means for offspring sex selection/enrichment). Using the mouse as a surrogate for humans in these studies, we will gain important knowledge that will be applicable to assisted reproduction, germ cell biology, and the developmental origins of adult disease. In the short term, the study of the effects on environmental toxicants on human and animal reproduction will uncover the mechanism of sex ratio distortion in dioxin- exposed humans. In the long run, the experiments funded by this project could lead to the development of beneficial pharmaceutical compounds to increase the ratio of female births of agriculturally important species.